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Shinya Nagamatsu - One of the best experts on this subject based on the ideXlab platform.

  • imaging exocytosis of single Insulin secretory granules with evanescent wave microscopy distinct behavior of granule motion in Biphasic Insulin release
    Journal of Biological Chemistry, 2002
    Co-Authors: Mica Oharaimaizumi, Yoko Nakamichi, Toshiaki Tanaka, Hitoshi Ishida, Shinya Nagamatsu
    Abstract:

    To study Insulin exocytosis by monitoring the single Insulin secretory granule motion, evanescent wave microscopy was used to quantitatively analyze the final stage of Insulin exocytosis with Biphasic release. Green fluorescent protein-tagged Insulin transfected in MIN6 beta cells was packed in Insulin secretory granules, which appeared to preferentially dock to the plasma membrane. Upon fusion evoked by secretagogues, evanescent wave microscopy revealed that fluorescence of green fluorescent protein-tagged Insulin brightened, spread (within 300 ms), and then vanished. Under KCl stimulation, which represents the 1st phase of release, the successive fusion events were seen mostly from previously docked granules for the first minute, followed by the recruitment of new granules to the plasmalemmal docking sites. Stimulation with glucose, in contrast, caused the fusion events from previously docked granules for the first 120 s, thereafter a continuous fusion (2nd phase of release) was observed over 10 min mostly from newly recruited granules that progressively accumulated on the plasma membrane. Thus, our data revealed the distinct behavior of the Insulin granule motion during the 1st and 2nd phase of release.

  • imaging exocytosis of single Insulin secretory granules with evanescent wave microscopy distinct behavior of granule motion in Biphasic Insulin release
    Journal of Biological Chemistry, 2002
    Co-Authors: Mica Oharaimaizumi, Yoko Nakamichi, Toshiaki Tanaka, Hitoshi Ishida, Shinya Nagamatsu
    Abstract:

    To study Insulin exocytosis by monitoring the single Insulin secretory granule motion, evanescent wave microscopy was used to quantitatively analyze the final stage of Insulin exocytosis with Biphasic release. Green fluorescent protein-tagged Insulin transfected in MIN6 β cells was packed in Insulin secretory granules, which appeared to preferentially dock to the plasma membrane. Upon fusion evoked by secretagogues, evanescent wave microscopy revealed that fluorescence of green fluorescent protein-tagged Insulin brightened, spread (within 300 ms), and then vanished. Under KCl stimulation, which represents the 1st phase of release, the successive fusion events were seen mostly from previously docked granules for the first minute, followed by the recruitment of new granules to the plasmalemmal docking sites. Stimulation with glucose, in contrast, caused the fusion events from previously docked granules for the first 120 s, thereafter a continuous fusion (2nd phase of release) was observed over 10 min mostly from newly recruited granules that progressively accumulated on the plasma membrane. Thus, our data revealed the distinct behavior of the Insulin granule motion during the 1st and 2nd phase of release.

Patrik Rorsman - One of the best experts on this subject based on the ideXlab platform.

  • Insulin granule dynamics in pancreatic beta cells
    Diabetologia, 2003
    Co-Authors: Patrik Rorsman, Erik Renstrom
    Abstract:

    Glucose-induced Insulin secretion in response to a step increase in blood glucose concentrations follows a Biphasic time course consisting of a rapid and transient first phase followed by a slowly developing and sustained second phase. Because Type 2 diabetes involves defects of Insulin secretion, manifested as a loss of first phase and a reduction of second phase, it is important to understand the cellular mechanisms underlying Biphasic Insulin secretion. Insulin release involves the packaging of Insulin in small (diameter ≈0.3 µm) secretory granules, the trafficking of these granules to the plasma membrane, the exocytotic fusion of the granules with the plasma membrane and eventually the retrieval of the secreted membranes by endocytosis. Until recently, studies on Insulin secretion have been confined to the appearance of Insulin in the extracellular space and the cellular events preceding exocytosis have been inaccessible to more detailed analysis. Evidence from a variety of secretory tissues, including pancreatic islet cells suggests, however, that the secretory granules can be functionally divided into distinct pools that are distinguished by their release competence and/or proximity to the plasma membrane. The introduction of fluorescent proteins that can be targeted to the secretory granules, in combination with the advent of new techniques that allow real-time imaging of granule trafficking in living cells (granule dynamics), has led to an explosion of our knowledge of the pre-exocytotic and post-exocytotic processes in the beta cell. Here we discuss these observations in relation to previous functional and ultra-structural data as well as the secretory defects of Type 2 diabetes.

  • a subset of 50 secretory granules in close contact with l type ca2 channels accounts for first phase Insulin secretion in mouse β cells
    Diabetes, 2002
    Co-Authors: Sebastian Barg, Lena Eliasson, Erik Renstrom, Patrik Rorsman
    Abstract:

    Capacitance measurements were applied to mouse pancreatic beta-cells to elucidate the cellular mechanisms underlying Biphasic Insulin secretion. We report here that only 10,000 granules are immediately available for release. The releasable granules tightly associate with the voltage-gated alpha(1C) Ca(2+) channels, and it is proposed that the release of these granules accounts for first-phase Insulin secretion. Subsequent replenishment of the releasable pool by priming of previously nonreleasable granules is required for second-phase Insulin secretion. The latter reaction depends on intragranular acidification due to the concerted action of granular bafilomycin-sensitive v-type H(+)-ATPase and 4,4-diisothiocyanostilbene-2,2-disulfonate--blockable ClC-3 Cl(-) channels. Lowering the cytoplasmic ATP/ADP ratio prevents granule acidification, granule priming, and refilling of the releasable pool. The latter finding provides an explanation to the transient nature of Insulin secretion elicited by, for example, high extracellular K(+) in the absence of metabolizable fuels.

  • the cell physiology of Biphasic Insulin secretion
    Neural Information Processing Systems, 2000
    Co-Authors: Patrik Rorsman, Lena Eliasson, Erik Renstrom, Jesper Gromada, Sebastian Barg, Sven Gopel
    Abstract:

    Glucose-stimulated Insulin secretion consists of a transient first phase followed by a sustained second phase. Diabetes (type II) is associated with abnormalities in this release pattern. Here we review the evidence that Biphasic Insulin secretion reflects exocytosis of two functional subsets of secretory granules and the implications for diabetes.

Jens Sandahl Christiansen - One of the best experts on this subject based on the ideXlab platform.

  • lower rates of hypoglycemia during maintenance treatment with Insulin degludec Insulin aspart versus Biphasic Insulin aspart 30 a combined analysis of two phase 3a studies in type 2 diabetes
    Journal of Diabetes, 2016
    Co-Authors: Jens Sandahl Christiansen, Leo Niskanen, Soeren Rasmussen, Thue Johansen, Greg Fulcher
    Abstract:

    Background Insulin degludec/Insulin aspart (IDegAsp) is a soluble coformulation of the basal analog Insulin degludec and the rapid-acting prandial Insulin aspart in a single injection. The present combined analysis of two Phase 3a trials compared the incidence of hypoglycemia in participants treated twice daily with IDegAsp or Biphasic Insulin aspart 30 (BIAsp 30). Methods Hypoglycemia data were analyzed from two similarly designed randomized controlled open-label treat-to-target Phase 3a clinical trials of adults with type 2 diabetes (T2D). Participants were treated twice daily with IDegAsp or BIAsp 30, with breakfast and their main evening meal. Results Over 26 weeks, the rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events were 19%, 57%, and 39% lower, respectively, with IDegAsp (n = 504) than BIAsp 30 (n = 364); estimated rate ratios were 0.81 (95% confidence interval [CI] 0.67, 0.98; P = 0.0341), 0.43 (95% CI 0.31, 0.59; P = 0.0001), and 0.61 (95% CI 0.26, 1.45; P = NS). The between-treatment differences were more pronounced during the maintenance period (≥16 weeks); compared with BIAsp 30, rates of overall confirmed, nocturnal confirmed and severe hypoglycemic events with IDegAsp were 0.69 (95% CI 0.55, 0.87; −31%; P = 0.0015); 0.38 (95% CI 0.25, 0.58; −62%; P < 0.0001), and 0.16 (95% CI 0.04, 0.59; −84%; P = 0.0061), respectively. Conclusions Compared with BIAsp 30 twice daily, IDegAsp twice daily provided similar improvements in glycemic control with a lower risk of hypoglycemia, particularly nocturnal hypoglycemia, in subjects with T2D previously treated with Insulin.

  • Insulin degludec Insulin aspart versus Biphasic Insulin aspart 30 in asian patients with type 2 diabetes inadequately controlled on basal or pre self mixed Insulin a 26 week randomised treat to target trial
    Diabetes Research and Clinical Practice, 2015
    Co-Authors: Shizuka Kaneko, Koichi Hirao, Thomas H Andersen, Francis C C Chow, Dong Seop Choi, Shinji Taneda, Yongsoo Park, Marianne Gall, Jens Sandahl Christiansen
    Abstract:

    Aims Insulin degludec/Insulin aspart (IDegAsp) is a soluble co-formulation of IDeg and IAsp. This pan-Asian, 26-week trial investigated efficacy and safety of IDegAsp vs Biphasic Insulin aspart 30 (BIAsp 30) in Asian adults with type 2 diabetes (T2DM), inadequately controlled on once- or twice-daily (BID) basal, premixed or self-mixed Insulin. Methods Participants (mean age 59.8 years, HbA1c 8.4%, FPG 7.9 mmol/L, BMI 25.4 kg/m(2)) were randomised 2:1 to BID IDegAsp (n=282) or BIAsp 30 (n=142) and continued existing metformin treatment. Insulins were administered with breakfast and main evening meal, titrated to a pre-breakfast and pre-main evening meal self-measured plasma glucose target of 4-5 mmol/L. Results IDegAsp achieved the primary endpoint of non-inferiority to BIAsp 30 for mean change in HbA₁c (estimated treatment difference [ETD] IDegAsp-BIAsp 30: 0.05% points [95% CI -0.10; 0.20]). IDegAsp was superior in lowering fasting plasma glucose (FPG) (ETD -1.06 mmol/L, 95% CI -1.43; -0.70, p Conclusion In Asian adults with T2DM, IDegAsp BID effectively improves long-term glycaemic control, and compared to BIAsp 30, provides superior reductions in FPG with a lower dose, and numerically less nocturnal hypoglycaemia.

  • comparison of Insulin degludec Insulin aspart and Biphasic Insulin aspart 30 in uncontrolled Insulin treated type 2 diabetes a phase 3a randomized treat to target trial
    Diabetes Care, 2014
    Co-Authors: Gregory Fulcher, Jens Sandahl Christiansen, Ganapathi Bantwal, Miroslawa Polaszewskamuszynska, Henriette Mersebach, Thomas H Andersen, Leo Niskanen
    Abstract:

    OBJECTIVE Insulin degludec/Insulin aspart (IDegAsp) is the first combination of a basal Insulin with an ultralong duration of action, and a rapid-acting Insulin in a single injection. This trial compared IDegAsp with Biphasic Insulin aspart 30 (BIAsp 30) in adults with type 2 diabetes inadequately controlled with once- or twice-daily (OD or BID) pre- or self-mixed Insulin with or without oral antidiabetic drugs. RESEARCH DESIGN AND METHODS In this 26-week, randomized, open-label, multinational, treat-to-target trial, participants (mean age 58.7 years, duration of diabetes 13 years, BMI 29.3 kg/m 2 , and HbA 1c 8.4% [68 mmol/mol]) were exposed (1:1) to BID injections of IDegAsp ( n = 224) or BIAsp 30 ( n = 222), administered with breakfast and the main evening meal and dose titrated to a self-measured premeal plasma glucose (PG) target of 4.0–5.0 mmol/L. RESULTS After 26 weeks, mean HbA 1c was 7.1% (54 mmol/mol) for both groups, with IDegAsp achieving the prespecified noninferiority margin for mean change in HbA 1c (estimated treatment difference [ETD] –0.03% points [95% CI –0.18 to 0.13]). Treatment with IDegAsp was superior in lowering fasting PG (ETD –1.14 mmol/L [95% CI –1.53 to –0.76], P P = 0.002). Fewer confirmed, nocturnal confirmed, and severe hypoglycemia episodes were reported for IDegAsp compared with BIAsp 30. CONCLUSIONS IDegAsp BID effectively improves HbA 1c and fasting PG levels with fewer hypoglycemia episodes versus BIAsp 30 in patients with uncontrolled type 2 diabetes previously treated with once- or twice-daily pre- or self-mixed Insulin.

  • ten years of experience with Biphasic Insulin aspart 30 from drug development to the latest clinical findings
    Drugs, 2012
    Co-Authors: Andreas Liebl, Jens Sandahl Christiansen, Vinay Prusty, P Valensi, Ryuzo Kawamori, Andrew J Palmer, Per Balschmidt, Robert Ligthelm, Viswanathan Mohan
    Abstract:

    Biphasic Insulin aspart 30 (BIAsp 30) includes 30% soluble rapid-acting Insulin aspart (IAsp) along with an intermediate-acting 70% protaminated IAsp that provides coverage of prandial and basal Insulin in a single injection. As BIAsp 30 has been available internationally for 10 years, this review provides a comprehensive overview of the discovery of BIAsp 30, its pharmacokinetic and pharmacodynamic profile, safety and efficacy outcomes from the clinical trial programme, 'real-life' clinical insights provided by observational study data, and cost effectiveness and quality-of-life information. These studies have demonstrated that BIAsp 30 once or twice daily is an appropriate option for Insulin initiation. BIAsp 30 also provides a switch option in patients on Biphasic human Insulin (BHI). Switching from BHI to BIAsp 30 is associated with improved postprandial glucose (PPG) and reduced nocturnal and major hypoglycaemia, although daytime hypoglycaemia is higher with BIAsp 30. Intensification of BIAsp 30 can be achieved by increasing the number of daily doses up to three times daily with meals. Therefore, BIAsp 30 provides an intensification option for individuals who are not achieving control with basal Insulin and would prefer the simplicity of a single Biphasic Insulin instead of progressing to a basal-bolus approach. BIAsp 30 has a simple dose-titration algorithm, which enables patients to effectively self-titrate their Insulin dose. Cost-effectiveness analyses have demonstrated that BIAsp 30 is cost effective or dominant compared with BHI 30 or Insulin glargine in a number of healthcare settings. In conclusion, BIAsp 30 offers a simple and flexible option for Insulin initiation and intensification that provides coverage of both fasting and prandial glucose.

  • risk for nocturnal hypoglycemia with Biphasic Insulin aspart 30 compared with Biphasic human Insulin 30 in adults with type 2 diabetes mellitus a meta analysis
    Clinical Therapeutics, 2009
    Co-Authors: Jaime A Davidson, Titus Gylvin, Greg Fulcher, Jens Sandahl Christiansen, Andreas Liebl, Robert Ligthelm, Paul Brown, Ryuzo Kawamori
    Abstract:

    Background: Insulin is recommended as a secondline treatment after diet and metformin fail to reach and/or maintain glycemic targets considered to minimize the risk for long-term diabetic complications. Hypoglycemia and the fear of developing hypoglycemia, however, remain substantial barriers to the initiation and optimal use of Insulin. Objective: The aim of this study was to compare Biphasic Insulin aspart 30 (BIAsp 30) with Biphasic human Insulin 30 (BHI 30) with respect to glycemic control and the risk for hypoglycemia using a metaanalysis of clinical trials comparing these Insulins in patients with type 2 diabetes mellitus (T2DM). Methods: We included all published and unpublished, randomized, controlled trials in adult patients with T2DM (treatment duration ≥12 weeks) for which individual patient data were available. All clinical databases and local trial registries of Novo Nordisk A/S (Soeborg, Denmark) were searched to identify clinical trials comparing the 2 products. The predefined primary end point of the study was the overall rate of nocturnal hypoglycemia (major, minor, and symptoms-only hypoglycemia occurring from 12:00–6:00 am). Hypoglycemia was analyzed using a negative binomial distribution model, accounting for exposure time. Glycemic end points were analyzed at 12 to 16 weeks of treatment using ANCOVA, adjusting for baseline. Secondary safety end points were the rates of major hypoglycemia (hypoglycemia requiring third-party assistance), minor hypoglycemia (symptoms confirmed by plasma glucose [PG] <3.1 mmol/L), daytime hypoglycemia (major, minor, and symptomsonly hypoglycemia occurring from 6:01 am–11:59 pm), overall hypoglycemia (the sum of all major, minor, and symptoms-only episodes), and change in weight from baseline to 12 to 16 weeks of treatment. Secondary efficacy end points were changes in glycosylated hemoglobin (HbA 1c ), fasting PG (FPG), postprandial PG increment (averaged over breakfast, lunch, and dinner), and Insulin dose. Results: Nine randomized, parallel or crossover trials were included (N = 1674; male sex, 57%; mean [SD] age, 61.0 [10.6] years; body mass index, 26.7 [4.6] kg/m 2 ; HbA 1c , 8.1% [1.4%]; duration of diabetes, 10.9 [7.9] years). Rates of overall hypoglycemia were not significantly different (rate ratio [RR] = 1.08; 95% CI, 0.94–1.24; P = NS) between treatments. BIAsp 30 had a 50% lower rate of nocturnal hypoglycemia than BHI 30 (RR = 0.50; 95% CI, 0.38–0.67; P < 0.01), whereas the rate of daytime hypoglycemia was 24% lower for BHI 30 (RR = 1.24; 95% CI, 1.08–1.43; P < 0.01). The likelihood of major hypoglycemia was significantly lower with BIAsp 30 com

Mica Oharaimaizumi - One of the best experts on this subject based on the ideXlab platform.

  • imaging exocytosis of single Insulin secretory granules with evanescent wave microscopy distinct behavior of granule motion in Biphasic Insulin release
    Journal of Biological Chemistry, 2002
    Co-Authors: Mica Oharaimaizumi, Yoko Nakamichi, Toshiaki Tanaka, Hitoshi Ishida, Shinya Nagamatsu
    Abstract:

    To study Insulin exocytosis by monitoring the single Insulin secretory granule motion, evanescent wave microscopy was used to quantitatively analyze the final stage of Insulin exocytosis with Biphasic release. Green fluorescent protein-tagged Insulin transfected in MIN6 beta cells was packed in Insulin secretory granules, which appeared to preferentially dock to the plasma membrane. Upon fusion evoked by secretagogues, evanescent wave microscopy revealed that fluorescence of green fluorescent protein-tagged Insulin brightened, spread (within 300 ms), and then vanished. Under KCl stimulation, which represents the 1st phase of release, the successive fusion events were seen mostly from previously docked granules for the first minute, followed by the recruitment of new granules to the plasmalemmal docking sites. Stimulation with glucose, in contrast, caused the fusion events from previously docked granules for the first 120 s, thereafter a continuous fusion (2nd phase of release) was observed over 10 min mostly from newly recruited granules that progressively accumulated on the plasma membrane. Thus, our data revealed the distinct behavior of the Insulin granule motion during the 1st and 2nd phase of release.

  • imaging exocytosis of single Insulin secretory granules with evanescent wave microscopy distinct behavior of granule motion in Biphasic Insulin release
    Journal of Biological Chemistry, 2002
    Co-Authors: Mica Oharaimaizumi, Yoko Nakamichi, Toshiaki Tanaka, Hitoshi Ishida, Shinya Nagamatsu
    Abstract:

    To study Insulin exocytosis by monitoring the single Insulin secretory granule motion, evanescent wave microscopy was used to quantitatively analyze the final stage of Insulin exocytosis with Biphasic release. Green fluorescent protein-tagged Insulin transfected in MIN6 β cells was packed in Insulin secretory granules, which appeared to preferentially dock to the plasma membrane. Upon fusion evoked by secretagogues, evanescent wave microscopy revealed that fluorescence of green fluorescent protein-tagged Insulin brightened, spread (within 300 ms), and then vanished. Under KCl stimulation, which represents the 1st phase of release, the successive fusion events were seen mostly from previously docked granules for the first minute, followed by the recruitment of new granules to the plasmalemmal docking sites. Stimulation with glucose, in contrast, caused the fusion events from previously docked granules for the first 120 s, thereafter a continuous fusion (2nd phase of release) was observed over 10 min mostly from newly recruited granules that progressively accumulated on the plasma membrane. Thus, our data revealed the distinct behavior of the Insulin granule motion during the 1st and 2nd phase of release.

Erik Renstrom - One of the best experts on this subject based on the ideXlab platform.

  • Insulin granule dynamics in pancreatic beta cells
    Diabetologia, 2003
    Co-Authors: Patrik Rorsman, Erik Renstrom
    Abstract:

    Glucose-induced Insulin secretion in response to a step increase in blood glucose concentrations follows a Biphasic time course consisting of a rapid and transient first phase followed by a slowly developing and sustained second phase. Because Type 2 diabetes involves defects of Insulin secretion, manifested as a loss of first phase and a reduction of second phase, it is important to understand the cellular mechanisms underlying Biphasic Insulin secretion. Insulin release involves the packaging of Insulin in small (diameter ≈0.3 µm) secretory granules, the trafficking of these granules to the plasma membrane, the exocytotic fusion of the granules with the plasma membrane and eventually the retrieval of the secreted membranes by endocytosis. Until recently, studies on Insulin secretion have been confined to the appearance of Insulin in the extracellular space and the cellular events preceding exocytosis have been inaccessible to more detailed analysis. Evidence from a variety of secretory tissues, including pancreatic islet cells suggests, however, that the secretory granules can be functionally divided into distinct pools that are distinguished by their release competence and/or proximity to the plasma membrane. The introduction of fluorescent proteins that can be targeted to the secretory granules, in combination with the advent of new techniques that allow real-time imaging of granule trafficking in living cells (granule dynamics), has led to an explosion of our knowledge of the pre-exocytotic and post-exocytotic processes in the beta cell. Here we discuss these observations in relation to previous functional and ultra-structural data as well as the secretory defects of Type 2 diabetes.

  • a subset of 50 secretory granules in close contact with l type ca2 channels accounts for first phase Insulin secretion in mouse β cells
    Diabetes, 2002
    Co-Authors: Sebastian Barg, Lena Eliasson, Erik Renstrom, Patrik Rorsman
    Abstract:

    Capacitance measurements were applied to mouse pancreatic beta-cells to elucidate the cellular mechanisms underlying Biphasic Insulin secretion. We report here that only 10,000 granules are immediately available for release. The releasable granules tightly associate with the voltage-gated alpha(1C) Ca(2+) channels, and it is proposed that the release of these granules accounts for first-phase Insulin secretion. Subsequent replenishment of the releasable pool by priming of previously nonreleasable granules is required for second-phase Insulin secretion. The latter reaction depends on intragranular acidification due to the concerted action of granular bafilomycin-sensitive v-type H(+)-ATPase and 4,4-diisothiocyanostilbene-2,2-disulfonate--blockable ClC-3 Cl(-) channels. Lowering the cytoplasmic ATP/ADP ratio prevents granule acidification, granule priming, and refilling of the releasable pool. The latter finding provides an explanation to the transient nature of Insulin secretion elicited by, for example, high extracellular K(+) in the absence of metabolizable fuels.

  • the cell physiology of Biphasic Insulin secretion
    Neural Information Processing Systems, 2000
    Co-Authors: Patrik Rorsman, Lena Eliasson, Erik Renstrom, Jesper Gromada, Sebastian Barg, Sven Gopel
    Abstract:

    Glucose-stimulated Insulin secretion consists of a transient first phase followed by a sustained second phase. Diabetes (type II) is associated with abnormalities in this release pattern. Here we review the evidence that Biphasic Insulin secretion reflects exocytosis of two functional subsets of secretory granules and the implications for diabetes.